The present invention relates to a process for continuously preparing 5-alkoxy-substituted oxazoles, in particular for continuously preparing 4-methyl-5-alkoxy-substituted oxazoles and also a process for preparing pyridoxine derivatives.
5-Alkoxy-substituted oxazoles are valuable synthetic building blocks in organic chemistry. 4-Methyl-5-alkoxy-substituted oxazoles have particular significance as important precursors for the synthesis and industrial production of vitamin B6 (Turchi et al., Chem. Rev. 1975, 75, 416).
A process which is economically viable and is operable on a large scale for preparing 5-alkoxy-substituted oxazoles, in particular 4-methyl-5-alkoxy-substituted oxazoles, is therefore of great significance.
It is known that xcex1-isocyanoalkanoate esters can be converted batchwise by thermal isomerization into the corresponding 5-alkoxy-substituted oxazoles.
Itov et al., Khimiko-Farmatsevticheskii Zhurnal, 1978, 12, 102 to 106 and Mishchenlo et al., Khimiko-Farmatsevticheskii Zhurnal, 1988, 7, 856 to 860 describe a batchwise thermal cyclization of xcex1-isocyanopropionate esters to give the corresponding 4-methyl-5-alkoxy-substituted oxazoles at 135xc2x0 C. The yields of 4-methyl-5-alkoxy-substituted oxazoles achieved by the use of various solvents are from 4 to 36%. The process has the disadvantage of low selectivity and thus the disadvantage that large amounts of by-products are formed. The most frequent by-products of this reaction are the unconverted reactant (yield: 33 to 55%) and also the rearranged xcex1-cyanopropionate ester (yield: 1 to 39%).
Maeda et al., Bull. Chem. Soc. Japan, 1971, 44, 1407 to 1410 disclose a batchwise thermal cyclization of various xcex1-isocyanocarboxylate esters to give the corresponding 5-alkoxy-substituted oxazoles at temperatures of from 150 to 180xc2x0 C. Depending on the substituents, yields of from 5.1 to 28.2% are achieved.
JP 54-20493 describes a batchwise process for preparing 4-methyl-5-alkoxy-substituted oxazoles by thermally cyclizing xcex1-isocyanopropionate esters at temperatures of 155 and 170xc2x0 C. in the presence of a tertiary amine. Although improved selectivities for the desired oxazoles are achieved (from 34 to 91.5%), the low conversion (from 11.1 to 49.4%) leads to yields which are still unsatisfactory.
All of the prior art processes have the disadvantage of low conversions and low selectivities and thus low yields of 5-alkoxy-substituted oxazoles. Owing to the batchwise processing method, the prior art processes only have low space-time yields.
It is an object of the present invention to provide a further process for preparing 5-alkoxy-substituted oxazoles which has advantageous characteristics, does not have the disadvantages of the prior art and delivers the 5-alkoxy-substituted oxazoles in high yields and high space-time yields.
We have found that this object is achieved by a process for continuously preparing 5-alkoxy-substituted oxazoles of the formula I, 
where
R1 is an unsubstituted or substituted C1-C6-alkyl radical and
R2 is hydrogen or an unsubstituted or substituted C1-C6-alkyl radical, which comprises
converting continuously added xcex1-isocyanoalkanoate esters of the formula II 
in the presence of continuously added assistants at temperatures above 80xc2x0 C. in a reactor to the 5-alkoxy-substituted oxazoles of the formula I and continuously removing the reaction products from the reactor.
The C1-C6-alkyl radicals R1 and R2 are each independently branched or unbranched, substituted or unsubstituted C1-C6-alkyl radicals, for example, substituted or unsubstituted methyl, ethyl, propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 1,2-dimethylbutyl, 2,3-dimethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethylbutyl or 2-ethylbutyl.
The nature of the substituents is not critical. The C1-C6-alkyl radicals may, depending on the possibility of free bonds, contain up to 6 substituents, preferably selected from the group consisting of aryl, hydroxyaryl, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94OH, xe2x80x94CN, xe2x80x94COOH, or halogen, in particular F or Cl.
In a preferred embodiment, the C1-C6-alkyl radicals R1 and R2 are unsubstituted.
Preferred R1 radicals include C1-C4-alkyl radicals, for example, methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl or tert-butyl, more preferably n-butyl.
Preferred R2 radicals include hydrogen and C1-C4-alkyl radicals, for example, methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl or tert-butyl, more preferably methyl.
Preference is given to the combination of the preferred radicals for R1 and R2, and particular preference to the combination of R1=n-butyl and R2=methyl.
In a particularly preferred embodiment of the process according to the invention, n-butyl xcex1-isocyanopropionate is accordingly converted into 4-methyl-5-n-butoxyoxazole.
The xcex1-isocyanoalkanoate esters of the formula II used in the process according to the invention may be of any desired purity.
The xcex1-isocyanoalkanoate esters of the formula II are prepared in a manner known per se from the corresponding formamido esters of the formula V 
by reacting them with phosphorus oxychloride or phosgene in the presence of bases. Common synthetic methods are described in Itov et al., Khimiko-Farmatsevticheskii Zhurnal, 1978, 12, 102-106; Maeda et al., Bull. Chem. Soc. Japan, 1971, 44, 1407-1410; Ugi et al., Chem. Ber. 1961, 94, 2814; Chem. Ber. 1960, 93, 239-248, Angew. Chem. 1965, 77, 492-504, Chem. Ber. 1975, 1580-1590, DE 30 29 231 A1 and J. Heterocyclic Chemistry 1988, 17, 705.
For the purposes of the present invention, assistants are chemical compounds, preferably chemical compounds which accelerate the cyclization reaction or shift the thermodynamic equilibrium in the direction of the desired product. Preferred assistants include cyclizing assistants selected from the group consisting of bases, alcohols and esters.
For the purposes of the present invention, bases are compounds having Brxc3x8nsted base properties. Preferred bases include tertiary amines, for example, triethylamine, triisopropylamine, tri-n-butylamine, dimethylcyclohexylamine, tris(2-ethylhexyl)amine, N-methylpyrrolidone, N,N,Nxe2x80x2Nxe2x80x2-tetramethyl-1,3-propanediamine, N,N-diethylaniline or N,N-dibutylaniline. Particular preference is given to the use of tri-n-butylamine as base.
Preferred alcohols are substituted or unsubstituted C1-C6-alkanols, for example, methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, n-pentanol or n-hexanol. Particular preference is given to the use of n-butanol as alcohol.
Preferred esters include substituted or unsubstituted C1-C6-alkyl C1-C6-alkanoates, for example, methyl acetate, ethyl acetate, propyl acetate, n-butyl acetate, tert-butyl acetate, hexyl acetate, methyl propionate, ethyl propionate, propyl propionate, n-butyl propionate, tert-butyl propionate, hexyl propionate, methyl butanoate, ethyl butanoate, propyl butanoate, n-butyl butanoate, tert-butyl butanoate, or hexyl butanoate. Particular preference is given to the use of n-butyl propionate as an ester.
The assistants may be used as individual compounds or in the form of mixtures. Preference is given to using the assistants as individual compounds.
Below 80xc2x0 C., no noticeable thermal cyclization takes place. The temperature of the conversion according to the invention is accordingly at least 80xc2x0 C.
In a preferred embodiment, the process according to the invention is operated at temperatures of from 100 to 200xc2x0 C., more preferably at temperatures of from 120 to 170xc2x0 C., most preferably at temperatures of from 130 to 170xc2x0 C.
The molar ratio of assistant to xcex1-isocyanoalkanoate ester of the formula II is not critical and is preferably from 10:1 to 0.05:1.
In the process according to the invention, the xcex1-isocyanoalkanoate esters of the formula II and the assistants are either added as a mixture or separately and continuously to a reactor, the xcex1-isocyanoalkanoate esters of the formula II are converted in the reactor to the 5-alkoxy-substituted oxazoles of the formula I and then the reaction products are withdrawn continuously from the reactor.
In principle, useful reactors include all reactors which facilitate a continuous method.
In a preferred embodiment of the process according to the invention, the reactor used is a tubular reactor. This continuously operated reactor preferably has no backmixing.
Accordingly, preference is given to a tubular reactor having a Bodenstein number greater than or equal to 50, which is determined in a manner known per se, for example, as described in Fitzer-Fritz, Technische Chemie, 3rd edition, Springer-Verlag, pages 288 ff.
Preference is given to the tubular reactor additionally having a theoretical tank number greater than or equal to 50.
The pressure in the tubular reactor and the residence time are not critical, although the reactor is preferably operated with pressure control and the residence time controlled by the metering in of the reactants.
The pressure in the tubular reactor is preferably at least 2 bar, ore preferably from 3 to 9 bar, particularly preferably from 4 to 7 bar, in particular 5 bar.
The residence time is preferably from 1 to 8 hours, more preferably from 2 to 6 hours, particularly preferably from 3 to 5 hours, in particular 4 hours.
In a particularly preferred embodiment of this process variant using a tubular reactor, the compounds of the formula II are advantageously only partially converted in the tubular reactor. The partial conversion is preferably from 40 to 70%, more preferably from 50 to 60%, in particular 54%.
In this preferred embodiment using a tubular reactor, it is particularly advantageous to feed the effluent of the tubular reactor into a continuously operated column and to continuously and distillatively separate it in the column into a low-boiling fraction comprising the compounds of the formula I and a high-boiling fraction comprising unconverted compounds of the formula II and assistants.
Preferred columns are the continuously operated reaction columns described below.
In this embodiment with the column attached downstream, a further conversion may be effected in the column attached downstream, as described below.
In a further preferred embodiment of this variant using the tubular reactor having a column attached downstream, the low-boiling fraction discharged from the column comprising unconverted compounds of the formula II and assistants is recycled into the reaction. This achieves a conversion of the compounds of the formula II of the overal process of 100%.
Another preferred embodiment of the continuous process according to the invention can be particularly advantageously carried out by removing the 5-alkoxy-substituted oxazoles of the formula I from the reaction mixture during the conversion in the reactor, i.e. simultaneously with the conversion. This removal is preferably likewise effected continuously.
There are many reactor designs which are useful for this preferred embodiment of the process according to the invention. Preferred reactors should have the property of facilitating a continuous conversion while simultaneously removing a reaction product.
Examples of useful reactors include stills having emplaced columns, extraction columns, bubble cap tray columns, membrane reactors, Lord reactors or reaction columns.
As is known to those skilled in the art, the term column, unless otherwise stated, refers to a column construction having a liquid phase.
Accordingly, an emplaced column refers only to a column construction without a liquid phase.
Reaction columns are preferably columns whose internals have a hold-up, for example, columns having trays, beds, structured packings or random packings.
In a particularly preferred embodiment of the process according to the invention, the reaction is carried out in a reaction column as reactor.
The reaction columns may be configured as desired by the construction and the internals. Particular preference is given to the use of a dividing wall column as the reaction column.
A reaction column which can be configured in highly varied ways has the characteristic of being a reactor which can simultaneously facilitate a conversion of reactants and the removal by rectification of the 5-alkoxy-substituted oxazoles of the formula I from the reaction mixture.
In this preferred embodiment employing a reaction column, it is also advantageous to set the rectification parameters in such a way that
A the xcex1-isocyanoalkanoate esters of the formula II are converted to the 5-alkoxy-substituted oxazoles of the formula I on the internals and, if present, in the liquid phase of the reaction column,
B the 5-alkoxy-substituted oxazoles of the formula I resulting from the conversion are continuously removed with the top stream or sidestream of the reaction column and
C the assistant and any high-boilers resulting from the conversion are removed continuously and independently of each other with the bottom stream or sidestream of the reaction column.
Depending on the design of the reaction column and the reactants used, this is achieved by different settings of the rectification parameters. Examples of suitable rectification parameters include temperature, pressure, reflux ratio in the column, configuration of the column and its internals, heat transfer and residence time, in particular in the liquid phase, and energy introduction, each of which may be optimized through routine experiments by those skilled in the art in such a way that the characteristics A, B and C are achieved.
In feature C, the assistants may in particular also be removed from the high-boilers in a second sidestream.
For the purposes of the present invention, a sidestream is the continuous discharge of a substance via a sidestream takeoff of the column.
In the process according to the invention, the pressure at the top of the column is also set in such a way that the temperature in the liquid phase and on the internals is at least 80xc2x0 C., preferably from 100 to 200xc2x0 C., more preferably from 120 to 170xc2x0 C.
Typically, the top pressure of the column is set to from 5 to 800 mbar, in such a way that the bottom pressure resulting from the column type used and the tanks of any column internals used is typically from 5 mbar to atmospheric pressure.
The residence time in the reaction column is typically from 10 minutes to 7 hours, preferably from 30 minutes to 4 hours.
It is possible that the 5-alkoxy-substituted oxazoles of the formula I form an azeotropic mixture with the assistants used so that the 5-alkoxy-substituted oxazoles of the formula I are removed via the top stream as an azeotropic mixture.
In this case, it is advantageous to set the top pressure and therefore also automatically the bottom pressure in the column in such a way that, depending on the 5-alkoxy-substituted oxazole of the formula I prepared and the assistant used, the fraction of assistant in the azeotrope in the top stream is as low as possible.
The assistant is removed from the top stream azeotrope in this case by a manner known per se, for example by a subsequent second rectification using a different pressure (two-pressure distillation).
For example, 4-methyl-5-n-butoxyoxazole prepared by the process according to the invention forms an azeotrope with the base tri-n-butylamine. When the top pressure is adjusted to 100 mbar, the azeotrope in the topstream is composed of 91% by weight of 4-methyl-5-n-butoxyoxazole and 9% by weight of tri-n-butylamine.
In this case, the tri-n-butylamine can be removed from the topstream azeotrope, for example, by a subsequent second rectification of the top pressure of 10 mbar.
The process according to the invention may be carried out in the presence or absence of solvents. In a preferred embodiment, the continuous process according to the invention is carried out without solvents.
In a further preferred embodiment, the process according to the invention is carried out in the presence of an inert solvent. Preferred inert solvents include nonpolar and polar aprotic solvents such as toluene, xylene or chlorobenzene, dichloromethane, dichloroethane, dichlorobenzene, ethylene carbonate, propylene carbonate, and in particular chlorobenzene.
When a solvent is used, the solvent may be added continuously to the column, for example, in a mixture with the assistant and the xcex1-isocyanoalkanoate esters of the formula II or each individual component may be added separately.
When an inert solvent is used in the process according to the invention, preference is given to setting the rectification parameters in such a way that
A the xcex1-isocyanoalkanoate esters of the formula II are converted to the 5-alkoxy-substituted oxazoles of the formula I on the internals and, if present, in the liquid phase of the reaction column,
B1 when the solvent has a higher boiling point than the 5-alkoxy-substituted oxazoles of the formula I resulting from the conversion, the 5-alkoxy-substituted oxazoles of the formula I are continuously removed with the top stream and the solvent is continuously removed via the sidestream or bottom stream of the reaction column,
B2 when the solvent has a lower boiling point than the 5-alkoxy-substituted oxazoles of the formula I resulting from the conversion, the 5-alkoxy-substituted oxazoles of the formula I are continuously removed with a sidestream and the solvent is continuously removed with the top stream of the reaction column and
C the assistant and any high-boilers resulting from the conversion are removed continuously and independently of each other with the top stream or sidestream of the reaction column.
The internals used in the reaction column may be of any design, for example, column trays, beds, random packings or structured packings.
Particularly advantageous column trays facilitate a long residence time of the liquid, and the residence time on the internals of the reaction column is preferably at least 30 min.
Examples of preferred column trays include valve trays, preferably bubble cap trays, or related designs, for example, tunnel cap trays, Lord reactors and other internals or Thormann trays.
Examples of preferred structured packings include structured packings of the Mellapack(copyright) (Sulzer), BY(copyright) (Sulzer), B1(copyright) (Montz) or A3(copyright) (Montz) types or packings having comparable designs.
The process according to the invention has the following advantages over the prior art:
The process according to the invention achieves selectivities of over 95% based on the xcex1-isocyanoalkanoate esters of the formula II used.
The conversion is almost 100%, so that the yields of 5-alkoxy-substituted oxazoles of the formula I is over 95%, based on the xcex1-isocyanoalkanoate esters of the formula II used.
A further advantage of the process is the continuous processing method. The space-time yield is distinctly greater than the prior art processes.
The process according to the invention provides a novel and advantageous contributory synthetic step in the process for preparing pyridoxine derivatives of the formula IX, 
in particular for preparing pyridoxine (vitamin B6; formula IX, R2=methyl).
The invention accordingly also relates to a process for preparing pyridoxine derivatives of the formula IX which comprises converting amino acids of the formula III 
to amino esters of the formula IV, 
converting the latter into formamido esters of the formula V, 
converting the latter into xcex1-isocyanoalkanoate esters of the formula II, 
converting the latter in a continuous process step according to the invention in the presence of assistants at temperatures above 80xc2x0 C. to 5-alkoxy-substituted oxazoles of the formula I 
reacting the latter with protected diols of the formula VI, 
where
R3 and R4 independently or R3 and R4 together are a protecting group of the hydroxy function to give the Diels-Alder adducts of the formula VII, 
and converting the latter by acid treatment and detachment of the protecting group to the pyridoxine derivatives of the formula IX.
The overall process is, apart from the novel, advantageous contributory step according to the invention for the continuous conversion of xcex1-isocyanoalkanoate esters of the formula II to 5-alkoxy-substituted oxazoles of the formula I, disclosed by Ullmann""s Encyclopedia of Industrial Chemistry 1996, Vol. A 27, pages 533 to 537.
The starting materials for the overall synthesis are inexpensive amino acids of the formula III, preferably alanine (R2=methyl). These are converted in a manner known per se, for example by acid-catalyzed esterification with the alcohols R1xe2x80x94OH, preferably n-butanol to amino esters of the formula IV. This esterification may also be cheaper than other methods, for example, by activating the acid function and base-catalyzed esterification. Further methods are described in U.S. Pat. No. 3,227,721.
The amino esters of the formula IV are converted in a manner known per se, for example as described in U.S. Pat. No. 3,227,721, to the formamido esters of the formula V.
The formamido esters of the formula V are then converted in a manner known per se, as described above, to the xcex1-isocyanoalkanoate esters of the formula II.
The xcex1-isocyanoalkanoate esters of the formula II are continuously converted, as described above, by the process according to the invention to the 5-alkoxy-substituted oxazoles of the formula I.
In the preferred overall process, this contributory step is carried out in the preferred embodiments, as described above.
The 5-alkoxy-substituted oxazoles of the formula I are then reacted with protected diols of the formula VI to give the Diels-Alder adducts of the formula VII.
This contributory step may be downstream of the process according to the invention, but may also be carried out by continuously adding the protected diols of the formula VI to the reactor of the process according to the invention simultaneously with the conversion of the xcex1-isocyanoalkanoate esters of the formula II to the 5-alkoxy-substituted oxazoles of the formula I. The addition may be carried out either in a mixture with the xcex1-isocyanoalkanoate esters of the formula II, the assistant and any solvent or as a separate component. In this case, the 5-alkoxy-substituted oxazole products are withdrawn directly in the form of their Diels-Alder adducts via the bottom discharge of the column.
The R3 and R4 radicals are each independently a protecting group, preferably an acid-labile protecting group, of the hydroxyl function.
In principle, any acid-labile protecting group may be used. Preferred acid-labile protecting groups are the acid-labile protecting groups for hydroxyl groups known from the literature (T. W. Greene, Protective Groups in Organic Synthesis, John Wiley and Sons N.Y., 1981, pages 14-71; P. J. Kocienski, Protecting Groups, Georg Thieme Verlag Stuttgart, 1994, pages 21-94).
In a preferred embodiment, the R3 and R4 radicals together may also form an acid-labile protecting group of both hydroxyl functions. The two hydroxyl functions preferably form a cyclic acetal with ketones or aldehydes, for example, acetone or isobutyraldehyde.
Subsequent acid treatments of the Diels-Alder adducts of the formula VII with elimination of the alcohol R1xe2x80x94OH results in aromatization to give the pyridoxine skeleton. The cleavage of the acid-labile protecting group(s) which is generally carried out by aqueous acid treatment delivers the pyridoxine derivatives of the formula IX, in particular pyridoxine (vitamin B6, R2=methyl).
The alcohol R1xe2x80x94OH and the protecting groups R3 and R4 may be recovered and reused in the overall process.
The use of the novel advantageous contributory step according to the invention in the overall process leads to an increase in the overall yield.
FIG. 1 illustrates the reaction colums""s various inlets and outlets for ester, additives, solvents, and the oxazole product. The meaning of the letters is as follows:
A side stream inlet into the column for propionate and amine feed;
B overhead stream outlet for, e.g., solvent removal or offtake of the oxazole;
C side stream offtake for the oxazole;
D side stream offtake for, e.g., the amine;
E bottom stream offtake for removing, e.g., the amine.